The total synthesis of the marine ladder toxin gambierol, efforts towards the synthesis of brevenal, and the development of a proton selective gramicidin A channel

The olefin ring closing metathesis (RCM) reaction has proven to be a powerful tool for carbon-carbon bond formation. Described is our success in applying this methodology to form seven and eight membered ether rings that are present throughout the entire family of marine ladder toxins.; Gambierol was isolated in 1993 by Yasumoto and co-workers from Gambierdiscus toxicus. Gambierol has been shown to be toxic to mice with symptoms resembling those of the ciguatoxins inferring the possibility that it is implicated in ciguatera poisoning. The structure consists of an octacyclic core containing 18 stereocenters and a partially skipped triene side chain. Utilizing our iterative C-glycoside/metathesis strategy we arrive at the A-C and F-H ring coupling precursors. Joining these two approximately equal sized fragments with 12 postcoupling steps we are able to complete the synthesis of the natural product.; Although membrane translocation of protons is an essential phenomenon in life, this process is poorly understood. The synthesis of a novel gramicidin A channel selective for protons may aid in studying this phenomena. In collaborations with the Cukierman group at Loyola University, we are rationally designing proton channels.; Recently a new polyether natural product from the red tide dinoflagellate Karenia brevis was isolated and characterized by Baden and co-workers. Brevenal appears to act as an "anti-toxin" protecting fish from the neurotoxic effects of brevetoxin exposure. A C-glycoside/metathesis approach developed in our laboratories is used to constuct the C-E rings and model the A-ring in a highly efficient manner. Currently efforts to complete the total synthesis are underway.